Theory and simulations for RNA folding in mixtures of monovalent and divalent cations
Theory and simulations for RNA folding in mixtures of monovalent and divalent cations
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DOI：
10.1073/pnas.1911632116
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发表时间：
2019-09
期刊：
影响因子：
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通讯作者：
H. T. Nguyen;N. Hori;D. Thirumalai
中科院分区：
文献类型：
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作者：
H. T. Nguyen;N. Hori;D. Thirumalai
RNA分子需要离子来折叠。不同大小和价态的离子如何驱动RNA分子折叠的问题尚未解决。在这里，我们通过创建一种基于多原子液体理论的方法来计算二价离子和磷酸盐基团之间的电势，从而在其解决方案中迈出了重要的一步。由此产生的模型，占内部和外部球协调的Mg 2+和Ca 2+的磷酸盐，当用于粗粒度的分子模拟，预测折叠自由能的一些RNA分子中存在的二价和一价离子，是非常符合实验。这项工作为探测序列和离子对DNA和合成聚电解质的影响奠定了基础。RNA分子在没有抗衡离子的情况下不能折叠。实验通常在一价和二价阳离子的存在下进行。如何处理含有两种离子类型的混合物的溶液对RNA折叠的影响几十年来一直是一个具有挑战性的问题。通过利用实验中使用的二价和一价离子之间的大浓度差，我们开发了一个理论的基础上的参考相互作用网站模型（RISM），这使我们能够明确地对待二价阳离子，同时保持由于一价离子的隐式屏蔽效应。我们的理论捕获了二价阳离子与磷酸基团的内壳和外壳配位，我们证明了这对RNA折叠热力学的准确计算至关重要。离子-磷酸盐相互作用的RISM理论与基于可转移粗粒度模型的模拟相结合时，使我们能够准确地预测在含有单价和二价离子的混合物中几个RNA分子的折叠。计算的折叠自由能和离子优先系数的RNA分子（假结，rRNA的片段，和腺嘌呤核糖开关的适体结构域）是在很宽的范围内的一价和二价离子浓度的实验非常一致。由于该理论是通用的，它可以很容易地用于研究离子和序列对DNA性质的影响。
Significance RNA molecules require ions to fold. The problem of how ions of differing sizes and valences drive the folding of RNA molecules is unsolved. Here, we take a major step in its solution by creating a method, based on the theory of polyatomic liquids, to calculate the potential between divalent ions and the phosphate groups. The resulting model, accounting for inner and outer sphere coordination of Mg2+ and Ca2+ to phosphates, when used in coarse-grained molecular simulations, predicts folding free energies for a number of RNA molecules in the presence of both divalent and monovalent ions that are in excellent agreement with experiments. This work sets the stage for probing sequence and ion effects on DNA and synthetic polyelectrolytes. RNA molecules cannot fold in the absence of counterions. Experiments are typically performed in the presence of monovalent and divalent cations. How to treat the impact of a solution containing a mixture of both ion types on RNA folding has remained a challenging problem for decades. By exploiting the large concentration difference between divalent and monovalent ions used in experiments, we develop a theory based on the reference interaction site model (RISM), which allows us to treat divalent cations explicitly while keeping the implicit screening effect due to monovalent ions. Our theory captures both the inner shell and outer shell coordination of divalent cations to phosphate groups, which we demonstrate is crucial for an accurate calculation of RNA folding thermodynamics. The RISM theory for ion–phosphate interactions when combined with simulations based on a transferable coarse-grained model allows us to predict accurately the folding of several RNA molecules in a mixture containing monovalent and divalent ions. The calculated folding free energies and ion-preferential coefficients for RNA molecules (pseudoknots, a fragment of the rRNA, and the aptamer domain of the adenine riboswitch) are in excellent agreement with experiments over a wide range of monovalent and divalent ion concentrations. Because the theory is general, it can be readily used to investigate ion and sequence effects on DNA properties.